Cibacron blue F3GA binds to dihydrofolate reductase from chicken liver and Lactobacillus casei in an 'electrostatic mode' and 'hydrophobic mode', respectively. Although the enzyme has a 'pseudo-dinucleotide fold', the blue dye does not bind at the proper nucleotide binding site to the enzyme from either species. Salt (NaCl) acts as an activator for the reaction catalyzed by dihydrofolate reductase (from chicken liver) if NADPH is used as the coenzyme and as an inhibitor if NADH is used as the coenzyme. 13 CL NMR studies reveal that this dichotomy in the kinetics is a result of the mutual exclusivity of chloride and NADPH binding at the active site of the enzyme while chloride and NADH binding to the enzyme are mutually inclusive.